DESCRIPTION: Transient viremia appearing after SHIV 89.6 infection evoked humor and cellular immune responses to SIV that protected against subsequent intravaginal SIV challenge. The presence of SIV specific CTLs in peripheral blood correlated with resistance to pathogenic SIV challenge. Because the vaccination regimen provided protection from pathogenic virus challenge and because the vaccine virus and challenge virus genes can be easily distinguished by PCR, this system provides an excellent opportunity to determine the mechanism of protection from challenge. The investigators will focus on traditional immune effector mechanisms, CD4+ T cell cytokine secretion patterns, and chemokine levels in immunized animals. Further they will determine if immune responses to viral regulatory gene products in the SHIV immunized animals are associated with protection from challenge. Important aspects of the proposed studies include experiments that determine if the route of SHIV immunization affects the ability of the animals to resist vaginal challenge with pathogenic SIV. This will determine whether stimulation of genital immune responses is necessary for protection against vaginal challenge. Subunit, immunization and VLP immunization strategies will be attempted to elicit mucosal and systemic immune responses comparable to those observed in animals immunized with nonpathogenic SHIV.